Nephrin is a cell surface signaling receptor protein that regulates podocyte function and plays a role in β-cell survival signaling; it is a protein necessary for the proper functioning of the renal filtration barrier. Nephrin belongs to a family of highly conserved proteins with a well characterized function as modulators of cell adhesion and guidance, and nephrin may have a role in metabolic pathways linked to podocyte and pancreatic β-cell survival. Nephrin is associated and partly co-localized with PI3-kinase in mouse islet β-cells and the mouse pancreatic beta-cell line (βTC-6 cells). Nephrin silencing abolishes Akt activation and increased susceptibility of cells to apoptosis. Glucose-induced changes in nephrin signaling may contribute to gradual pancreatic β-cell loss in type 2 diabetes. This suggests a role for nephrin as an independent modulator of podocyte and pancreatic β-cell nutrient sensing in the fasting state and the potential of nephrin as a drug target in diabetes.